The autoimmune aetiology of unexplained chronic pain, 2021, Goebel et al

ola_cohn · Dec 15, 2021

Abstract
Chronic pain is the leading cause of life years lived with disability worldwide. The aetiology of most chronic pain conditions has remained poorly understood and there is a dearth of effective therapies. The WHO ICD-11 has categorised unexplained chronic pain states as ‘chronic primary pains’ (CPP), which are further defined by their association with significant distress and/or dysfunction. The new mechanistic term, ‘nociplasticic pain’ was developed to illustrate their presumed generation by a structurally intact, but abnormally functioning nociceptive system. Recently, researchers have unravelled the surprising, ubiquitous presence of pain-sensitising autoantibodies in four investigated CPP indicating autoimmune causation. In persistent complex regional pain syndrome, fibromyalgia syndrome, chronic post-traumatic limb pain, and non-inflammatory joint pains associated with rheumatoid arthritis, passive transfer experiments have shown that either IgG or IgM antibodies from patient-donors cause symptoms upon injection to rodents that closely resemble these clinical disorders. Targets of antibody-binding and downstream effects vary between conditions, and more research is needed to elucidate the details. The central nervous system appears largely unaffected by antibody binding suggesting that the clinically evident CNS symptoms associated with CPP might arise downstream. In this narrative review pertinent findings are described, and it is suggested that additional symptom-based disorders might be examined for the contribution of antibody-mediated autoimmune mechanisms.

Authors: Andreas Goebel, David Andersson, Suzsanna Helyes, David Clark, Debra Dulake, Camilla Svensson

Paywall
https://www.sciencedirect.com/science/article/abs/pii/S1568997221002974?via=ihub

Hutan · Dec 15, 2021

I haven't got past the introduction, but it's interesting to see this, and see where some of the authors are based:

Furthermore, although psychological and social factors are consistently associated, their association is considered bidirectional [4], and persuasive brain mechanisms responsible for the translation of distress experiences into pain perception have yet to be identified [5]. Chronic pain conditions typically come without systemically elevated inflammatory markers, and most patients test negative in standard autoantibody assays. In other words, symptoms that profoundly affect billions of people across the globe have remained unexplained. New approaches to their understanding are needed.
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Andreas Goebel a
David Andersson b
Suzsanna Helyes c
DavidClark d
Debra Dulake e
Camilla Svensson f
a Pain Research Institute, Institute for Life Course and Medical Sciences, University of Liverpool, UK and Walton Centre NHS Foundation Trust, Liverpool, UK
b Institute of Psychiatry, Psychology and Neuroscience, Wolfson Centre for Age Related Disease, King's College, London, UK
c Department of Pharmacology and Pharmacotherapy, Medical School & Szentágothai Research Centre, University of Pécs, Pécs, Hungary (@Wyva- perhaps of interest)
d Anaesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, USA
e Patient Insight Partner, Mansfield, UK
f Department of Physiology and Pharmacology, Center for Molecular Medicine, Karolinska Institutet, Stockholm 171 76, Sweden

Also interesting to see a 'Patient Insight Partner' in the author list.

Hutan · Dec 15, 2021

So the process is you take presumed pathogenic immunoglobulins from the patients and inject them into the rodents, hope that the immunoglobulins are affecting a pathway common to humans and rats, and observe the rats for signs of the symptoms the humans complain of.

The general principle of passive transfer experiments is that presumed pathogenic human serum-immunoglobulins are isolated from patients and transferred to rodents; the animals are then assessed for signs of the disease (Fig. 1). It is possible to achieve success when key immune targets and downstream pathways are preserved between human and rodent; successful transfer is indicated by the reproduction of core features of the disease, highlighting autoimmune causation [9]. A prominent example of successful passive transfer are classical results in myasthenia gravis where rodents develop muscle weakness when injected with patient-derived IgG [10]. It was hypothesised that immunoglobulin passive transfer may identify a directly causative role of autoantibodies in CPP.
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They make some very strong claims - most or all patients from the various chronic pain conditions had troublesome antibodies, while none of the the healthy controls did.

First experiments indicated subtle abnormalities in rodent behaviour [8,11] but over the past decade, passive transfer experiments in four CPP models have proven more successful than anticipated. While experimental paradigms differed between conditions, materials from most or all patients, within each tested CPP diagnostic sub-group, were shown to harbour pathogenic pronociceptive antibodies whereas people without chronic pain always tested negative. These experiments have satisfied Witebsky's autoimmunity criteria for each investigated condition, and have provided a novel mechanistic direction for future drug development [9].
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This was interesting about CRPS - most patients spontaneously recover, but the unlucky few who don't seem to be stuck with it.

CRPS (formerly called Reflex Sympathetic Dystrophy, RSD) is a regional CPP which typically arises after distal limb trauma [12]. Most patients (85%) will spontaneously improve within 12–18 months post trauma. However, subsequent improvement is uncommon [13].
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The paper that I could see only had what they call 'Section snippets'. I think you have to pay to read the whole article.

So, I don't know. I'd love an autoantibody explanation to be true, even if just for the people with chronic pain conditions. But I don't think we have seen any convincing papers on autoantibodies for fibromyalgia or other chronic pain conditions yet? Maybe it's worth having a look at the studies they cite as providing evidence for their idea.

Andy · Dec 15, 2021

A number of the same authors were also involved in this paper, Passive transfer of fibromyalgia symptoms from patients to mice, 2021, Goebel et al

alktipping · Dec 16, 2021

"Chronic pain is the leading cause of life years lived with disability worldwide." should that not read as chronic health conditions that have chronic disabling pain as a symptom . or chronic pain is a disabling symptom . or am i being to sensitive to their choice of language.

Arnie Pye · Dec 16, 2021

My bolding...

ola_cohn said: ↑

In persistent complex regional pain syndrome, fibromyalgia syndrome, chronic post-traumatic limb pain, and non-inflammatory joint pains associated with rheumatoid arthritis, passive transfer experiments have shown that either IgG or IgM antibodies from patient-donors cause symptoms upon injection to rodents that closely resemble these clinical disorders.
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My mother had rheumatoid arthritis. By the end of her life her hands and some other joints were distorted, knobbly, partially wasted, as is so often the case with rheumatoid arthritis. The fact that the inflammation wasn't obvious at the start doesn't mean she didn't have rheumatoid arthritis. It just meant that it took a while to develop obvious visible severity.

Is that how medicine always works nowadays? If a condition hasn't progressed to be visible it isn't real?

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